Human cytomegalovirus (HCMV) infection represents the most common viral infection transmitted in-utero and is a significant cause of neurodevelopmental disorders in children. The rate of congenital HCMV infection ranges from 0.2-1.0% of live births in the US and exceeds 1% in many parts of the world. Although maternal infection during pregnancy (primary maternal infection) represents a significant risk for virus transmission to the fetus and disease, infection and transmission to the fetus in women with existing immunity to this virus (non-primary maternal infection) is frequent. Disease in babies infected following non-primary maternal infection is well documented. Worldwide, including most US populations, the disease burden in infected infants born to women with non-primary infections exceeds that of offspring of women with primary maternal infection. In this proposal we will explore two mechanisms of non-primary maternal infections, reinfection with new strain of viruses and recurrence/reactivation of a persistent infection. Our goals are to define virological characteristics of non-primary infections and parameters of HCMV specific immunity in a highly seroimmune population in which non-primary maternal infections account for the vast majority of infected babies. We will also determine the incidence of the most common long term sequelae of congenital HCMV infection, hearing loss, in infected babies. We anticipate these studies will help identify host responses associated with intrauterine transmission and damaging fetal infections in this population of women with non-primary infection and could aid in the rationale development of effective prophylactic and possibly therapeutic vaccines to limit the morbidity from this congenital infection. PUBLIC HEALTH RELEVANCE: This project will investigate the characteristics of human cytomegalovirus infection in a population of women in which over 98% have immunity to this virus. Even in the presence of immunity, these women still transmit virus to their developing offspring and about 10% of infected babies develop hearing loss, the most common sequelae of this congenital infection. Current vaccine strategies will not prevent this type of congenital infection and in almost every part of the world, including the US, infected infants born to immune mothers represent the largest contribution to the overall disease burden of this infection. Our goals are to elucidate the mechanisms responsible for transmission of virus in these immune women in order to more rationally design strategies that could prevent infection of the developing fetus with this virus.